Cinnamic acid

Pharmacology of Cinnamic acid found in Daarusitaa-Cinnamon (Cinnamomum verum)
Dr. Hemant Vinze M. S. 
Introduction

Daarusitaa in Ayurveda is Cinnamon in English.  In the West Cinnamon or cassia is a spice obtained from the inner bark of several tree species from the genus Cinnamomum. In the Orient however Daarusita has more medicinal value than a mere spice.

In the taxonomic terminology it is known by various names. However Cinnamomum verum is considered as true cinnamon by plant taxonomists. [1]

Daarusitaa-Cinnamon contains many pharmacologically active phytochemicals.  Cinnamic acid is one of them.

Cinnamic acid is a white crystalline organic compound, slightly soluble in water, and freely soluble in many organic solvents. It is classified as an unsaturated carboxylic acid. It occurs naturally in a number of plants.

Cinnamic acid is obtained from oil of cinnamon or from balsams such as storax. Cinnamic acid has a honey like odor. In pharmaceuticals it is a popular flavoring agent. [2]

Molecular formula: C9H8O2
Structural formula:







Pharmacokinetics

After oral administration cinnamic acid is quickly absorbed in stomach and intestine. It is completely metabolized in the liver before it is absorbed in the blood and is excreted in urine. [3]

Anti-inflammatory activity

Cinnamic acid is not used as a medicine or a drug. Derivatives and esters of cinnamic acid have anti-inflammatory, antioxidant and               cytotoxic properties. They are lipooxigenase inhibitors. Some derivatives and esters are tested for anticancer activities. [4]

Cinnamic acid derivatives especially those with phenolic hydroxyl group are strong antioxidants. They have several health benefits. They show anti-inflammatory, antioxidant, antibacterial, antiviral, antifungal properties [5].

Like cinnamic acid, its derivative 7-O-Cinnamoylmorroniside exhibits a strong anti-inflammatory activity. E-selectin, also known as   CD62 antigen-like family member E (CD 62 E) is a cell adhesion molecule expressed only on endothelial cells activated by cytokines. E-selectin plays an important role in inflammations. Cinnamoylmorroniside is a potent inhibitor of tumor necrosis factor alpha (TNF-α) - induced expression. [6]
  
Antioxidant activity

Derivatives of cinnamic acid show higher antioxidant activity than that of cinnamic acid. This is due to the presence of vinyl fragments. This property of the derivatives attracts attention of pharma industry for the development of new drugs especially for the treatment of pathologies related to lipid peroxidation in cellular membranes. [7]

Cinnamic acid derivatives especially those with phenolic hydroxyl group are strong antioxidants. They have several health benefits. They show anti-inflammatory, antioxidant, antibacterial, antiviral, antifungal properties. [8]

Antimicrobial activity

Most of the cinnamic acids, their esters, amides, aldehydes and alcohols show significant inhibition of growth of several bacterial and fungal species. The data of antimicrobial species is however inadequate. The search is on to develop antitubercular drug with hybrids between cinnamic acids and biologically active other antimicrobial compounds. [9]

Recently a series of esters, substituted derivatives and amides of cinnamic acid were synthesized. They showed antibacterial activity   against Gram negative organisms. They were especially effective against Escherichia coli and the fungus Candida albicans. [10]      

Antiviral activity

Cinnamic acid, trans-cinnamic acid and derivatives of cinnamic acid exhibit antiviral activity against many viruses. They are not virucidal but inhibit the replication cycle of viruses. [11]
   
Antifungal Activity                       

In a study Kim JH et al found antifungal activity of cinnamic acid and its derivatives. Of these 4-chloro cinnamate showed highest antifungal activity against C. rolfsii.  [12]   

Antimalarial activity

Cinnamic acid and its derivatives inhibit the transport of monocarboxylate across erythrocyte and mitochondrial membranes. They also inhibit parasite growth and are effective at ring and trophozite stages of the malarial parasite. Antimalarial activity of cinnamic acid could be due to inhibition of lactate transport or of mitochondrial respiration. Since cinnamic acid and its derivatives are also noxious to host cells they cannot be used to develop novel antimalarial drugs. However they are useful tools in research.  [13]

Actions on the skin

By causing irreversible damage to DNA leading to cell death, cinnamic acid and its derivatives induce apoptosis in human melanoma cells. In a study, human melanocyte cell line (HT-144) and human melanocyte cell line derived from blue nevus (NGM) were exposed to cinnamic acid. HT-144 cells were sensitive to cinnamic acid treatment while NGM cells were less sensitive. The cell death was due to aberrations caused in DNA leading to non-viability of cells. This study shows that cinnamic acid has effective antiproliferative activity against melanoma cells. Further study is necessary to develop anticancer drugs from cinnamic acid. [14]

Actions on CNS

Fourteen derivatives of cinnamic acid were tested for their effects on central nervous system. All of them prolonged the sleep induced by phenobarbitone. This shows that cinnamic acid derivatives are central nervous system depressants. [15]

To evaluate effects of cinnamic acid and its derivatives, experiments were performed on slices of rat brains of either sex. Increase in the concentration of potassium ions results in the increases in the oxygen uptake by respiring slices of cerebral cortex.                   Cinnamic acid and its derivatives suppressed the potassium activated oxygen uptake in brain slices. [16]

Halogenated cinnamic acid derivatives show highest CNS depressant activity. [17]

Actions on CVS

Cinnamic acid and its derivatives viz. 3, 4-dihydrocinnamate i.e. L-serine methyl ester and L-aspartic acid show lipid lowering property. By using clofibrate as a positive control Kim and co-workers reported that cinnamic acid derivatives lowered atherogenic index and increased serum HDL. The derivatives also lowered hepatic cholesterol.
By inhibiting human acetyl-Co A, cellular cholesterol storage and LDL-oxidation these derivatives prevent atherosclerosis. [18] 

Actions on RS

A series of novel cinnamic acid derivatives was synthesized. They suppress the growth of A 549 lung cancer cells effectively. [19]

Actions on GI System

Trans-cinnamic acid (tCA) was observed to inhibit the proliferation of colon carcinoma cells. No toxic changes were found in the heart, lung, colon, liver, kidney or bone marrow following histopathological examination. [20]

Recently cinnamyl sulphonamide hydroxamate, a novel derivative of cinnamic acid has been synthesized. Histone deacetylases (HDAC)    are a group of enzymes that regulate DNA expression. The hydroxamate derivatives of cinnamic acid are inhibitors of HDAC enzyme. By acting through HDAC enzyme inhibition hydroxamate derivatives of cinnamic acid act against adenocarcinoma of the colon. [21]
                    
Actions on the Liver

Trichlorfon is hepatotoxic, mutagenic pesticide. Cinnamic acid at 30 and 60 mg/kg body weight protects the liver against toxicity caused by trichlorfon. Cinnamic acid can cure trichlorfon-induced hepatotoxicity. [22]

Pre-treatment with cinnamic acid at 2.8 mg/kg body weight was found to protect the liver against mutagenic effects of cyclophosphamide.   Cinnamic acid also reversed the hepatocyte damage caused by cyclophosphamide treatment. [23]

At 20 mg/kg body weight, cinnamic acid protects the liver from cisplatin-induced hepatotoxicity. Therefore cinnamic acid can be considered to be considered to be a potential candidate for hepato-renal protection against cisplatin-induced toxicity. [24]

At 28 and 56 mg/kg body weight cinnamic acid protects the liver from acute hepatocyte damage caused by endoxan. This activity is much superior to protection offered by vitamin C. Cinnamic acid even prevents the necrosis of hepatocytes caused by endoxan. [25]

Actions on Metabolism/ Obesity

Obesity is a chronic metabolic and proinflammatory disorder associated with hyperlipidemia (dyslipidemia), diabetes mellitus, hypertension, atherosclerosis, cardiovascular disease, non alcoholic fatty liver disease, nephropathy and cancer. In experimental studies on animal models, cinnamic acid at 30 mg/kg body weight for 7days, normalized the body weight in high fat diet fed animals, lipid profile reverted back to normal levels the activities of lipase and angiotensin converting enzyme. Cinnamic acid also prevented the vasoconstriction of aorta as evidenced on echocardiography. Cinnamic acid also prevented the steatosis of the liver.  [26]                   
Cinnamates and various other derivatives of cinnamic acid such as compound b and c also lower the raised lipid levels in plasma as does cinnamic acid. Whereas cinnamic acid lowered hepatic-HMG-CoA reductase activity, its synthetic derivatives (a and b) do not affect hepatic-HMG-CoA reductase activity [27]

Protein Tyrosine Phosphatase 1B (PTP1B) inhibitors are much sought after drugs for the treatment of type 2 diabetes and obesity. Cinnamic acid and its derivatives (o-Hydroxycinnamic acid 25 µM and p-Hydroxycinnamic acid 25 µM) being PTP1B inhibitors are   useful for the treatment of type 2 diabetes and obesity. [28]

A series of cinnamic acid derivatives were synthesized. They inhibit LDL-oxidation, acyl-Co A cholesterol acyltransferase-1 and-2 activities. Thus cinnamic acid derivatives are useful as anti-atherosclerotic agents [29]


Antidiabetic Activity

Cinnamic acid derivatives show strong hypoglycemic activity. [30]

At doses of 40-100 mg/kg body weight, by stimulating insulin secretion from the β cells of the pancreas p-methoxycinnamic acid lowers blood sugar in normal and streptozotocin-induced diabetic rats. [31]

Cinnamic acid derivatives show insulin releasing properties. [32]

By increasing calcium influx via L-type calcium channels p-methoxycinnamic acid stimulates insulin secretion from the β cells of the pancreas but not through the closure of ATP-sensitive K-channels. 

Furthermore based on several in vitro studies researchers found that cinnamic acid and its derivatives act on different mechanism of actions including stimulation of beta cells to secrete insulin, improving the function of beta cells of the pancreas, increased insulin signaling pathway, inhibition of hepatic gluconeogenesis, enhanced glucose uptake, delay of carbohydrate digestion and glucose absorption and inhibition of protein glycation. However bioavailability of cinnamic acid and its derivatives is low and not much study has been done on human subjects. Therefore these useful agents have limited use in clinical practice. [33], [34]                       

Hydrocinnamic acid derivatives act as supplements to other conventional oral hypoglycemic agents and may reduce the secondary complications caused by oral hypoglycemic agents. [35] 

Actions on Male Reproductive system

Cinnamic acid and its derivatives have higher affinity for α 1 A-adrenoceptors. Researchers are investigating their role and importance in benign hyperplasia of prostate. [36]  

Antitumor Activity

Products derived from cinnamic acid such as cinnamoyl acid, esters, amides, hydrazides and related derivatives show cytotoxic and antitumor activity. [37]

Cinnamic acid and its derivatives have inspired researcher to design inhibitors of oncogenic protein kinases. The mode of inhibition may vary from ATP-competitive to non-competitive one. [38]

Analogues of cinnamic acid benzyle amide exhibit pleiotropic effects on cancer cells. [39]

Cynnamic acid and its derivatives induce cell cycle arrest in cancer cell lines [40]

Cinnamyl sulphonamide hydroxamate derivatives (HDAC) inhibitors show anti-angiogenic, anti-cancer and anti-metastatic activities in human cancer cells. [41]

Toxicity of cinnamic acid

Cinnamic acid is a compound of low toxicity. Its compounds aldehyde, alcohol, esters and those containing cyano and fluoro moieties are more toxic. [42]

References:

1. https://en.wikipedia.org/wiki/Cinnamon

2. Cinnamic acid in its pure form is a precursor of famous sweetener aspartame.
https://en.wikipedia.org/wiki/Cinnamic_acid

3. Yingrong Chen et al, Pharmacokinetics and bioavailability of cinnamic acid after oral administration of Ramulus cinnamomi in rats, https://www.researchgate.net/publication/26234600  

4. Hadjipavlou-Litina D et al, Aryl-acetic and cinnamic acids as lipoxigenase inhibitors with antioxidant, anti-inflammatory and anticancer activity. Methods Mol Biol, 2015; 1208:361-377  

5. Sova M et al, Antioxidant and antimicrobial actiities of cinnamic acid derivatives, Mini Rev Med Chem, 2012 Jul; 12(8): 749-67 

6. W Sun et al, Synthesis and properties of cinnamic acid series organic UV ray absorbents-interleaved layered double hydroxides, Materials Letters, 2007, 61, 1881-1884  

7. N Fausta et al, Benzoic acid and cinnamic acid derivatives as antioxidants: Structure-activity relation, J Agric. Food Chem; 1999, 47, 1453-1459.   

8. Sova M et al, Antioxidant and antimicrobial actiities of cinnamic acid derivatives, Mini Rev Med Chem, 2012 Jul; 12(8): 749-67 

9. Guzman JD, Natural cinnamic acids, synthetic derivatives and hybrids with antimicrobial activity, Molecules, 2014 Nov 25;  19(12): 19292-349 

10. Narasimhan B et al, Esters, amides and substituted derivatives of cinnamic acid: synthesis, antimicrobial activity and QSAR investigations, Eur J Med Chem, 2004 Oct; 39(10): 827-834 

11. Prateek Sharma, Cinnamic acid derivatives: A new chapter of various pharmaceutical activities, J Chem. Pharm. Res., 2011, 3(2): 403-423    

12. Prateek Sharma, Cinnamic acid derivatives: A new chapter of various pharmaceutical activities, J Chem. Pharm. Res.,   2011, 3(2): 403-423   

13. Prateek Sharma, Cinnamic acid derivatives: A new chapter of various Pharmaceutical activities, J Chem. Pharm. Res., 2011, 3(2): 403-423  

14. Evandro Luis de Oliveira Niero et al, Cinnamic acid induces apoptotic cell death and cytoskeleton disruption in human melanoma cells, J Exp Clin Cancer Res. 2013 May; 32(1):21

15. MNA Rao, PN Raman, DR Kulkarni, 1987; Central nervous system depressant activity of cinnamic acid derivatives, www.ijpsonline.com

16. Surendra S. Parmar, J. P. Barthwal, Effect of cinnamic acid on potassium stimulated respiration in rat brain slices, Biochemical Pharmacology, 1966, Volume 15, Issue 11, November 1966, pages 1888-1890    

17. Prateek Sharma, Cinnamic acid derivatives: A new chapter of various pharmaceutical activities, J Chem. Pharm. Res., 2011, 3(2): 403-423     

18. Prateek Sharma, Cinnamic acid derivatives: A new chapter of various pharmaceutical activities, J Chem. Pharm. Res.,  2011, 3(2): 403-423                           
19. Zhou XW et al, Synthesis of 6-cinnamoyl-2H-benzo[b][1,4]oxazin-3[4H]-ones and their effects on A549 lung cancer cell  growth, Eur J Med Chem. 2014 May 22; 79:95-101 

20. Bingyan Zhu et al, Inhibition of histone deacetylases by trans-cinnamic acid and its antitumor effect against colon cancer  xenografts in athymic mice, Mol Med Rep. 2016 May; 13(5): 4159-4166

21. Reddy ND et al, in vitro and in vivo evaluation of novel cinnamyl sulfonamide hydroxamate derivative against colon adenocarcinoma, Chem Biol Interact. 2015 May 25; 233:81-94.    
                    
22. Nibal et al, Cinnamic acid activity towards Trichlorfon pesticide and liver function enzymes in rat, Magazine of Al-Kufa University for Biology; Vol. 6, No 1, Year 2014.    
23. Nibal et al, Biochemical and Hepatoprotective Effects of Pure Cinnamic acid Against Cyclophosphamide in White Rats, http://www.iajs.net/iasj?func=fulltext&aId=60974   

24. Amany A et al Cinnamic acid Attenuates Cisplatin-Induced Hepatotoxicity and Nephrotoxicity, Journal of Basic and Environmental Sciences, 3(2016)1-9 

25. Nibal K et al, Liver histopathological of purification cinnamic acid activity against endoxan in mice, Journal of Genetic and Environmental Resources Conservation, 2014; 2(1): 22-29   

26. Kais Mnafgui et al, Anti-obesity and cardioprotective effects of cinnamic acid in high fat diet-induced obese rats, J Food Sci Technol. 2015 Jul; 52(7): 4369-4377    

27. Prateek Sharma, Cinnamic acid derivatives: A new chapter of various pharmaceutical activities, J Chem. Pharm. Res.,  2011, 3(2): 403-423   

28. Adisakwattana S et al, In vitro effects of cinnamic acid derivatives on protein tyrosine phosphatase 1B, J Enzyme Inhib Med Chem. 2013 Oct; 28(5): 1067-72    

29. Lee S et al, Synthesis of cinnamic acid derivatives and their inhibitory effects on LDL-oxidation, aceyl-Co A: cholesterol acyltransferase-1 and-2 activity and decrease of HDL-particle size, Bioorg Med Chem Lett, 2004 Sep 20; 14(18):4677-4681 

30. Prateek Sharma, Cinnamic acid derivatives: A new chapter of various pharmaceutical activities, J Chem. Pharm. Res., 2011, 3(2): 403-423  

31. Yibchok-anun S et al, Insulin-secretagogue activity of p-methoxycinnamic acid in rats, perfused rat pancreas and pancreatic beta-cell line, Basic Clin Pharmacol Toxicol. 2008 May; 102(5): 476-482    

32. Adisakwattana S et al, Insulin-releasing properties of a series of cinnamic acid derivatives in vitro and in vivo, J Agric Food Chem. 2008 Sep 10; 56(17): 7838-7844

33. Adisakwattana S et al, Mechanisms of p-methoxycinnamic acid-induced increase in insulin secretion, Horm Mrtab Res  2011 Oct; 43(11): 766-73 
  
34. Adisakwattana S, Cinnamic acid and its Derivatives: Mechanisms for Prevention and Management of Diabetes and its   Complications; Nutrients. 2017 Feb 21; 9 (2).     

35. Prabhakar PK et al, Interaction of cinnamic acid derivatives with commercial hypoglycemic drugs on 2-deoxyglucose  uptake in 3T3-L1 adepocytes, J Agric Food Chem. 2011 Sep 28; 59(18): 9835-44    

36. Chang HK et al, Stimulatory effect of cinnamic acid analogues on alpha 1A-adrenoceptors in-vitro, J Pharm Pharmacol 2003 Jun; 55(6): 833-837         

37. De P et al, Cinnamic acid derivatives as anticancer agents-a review, Curr Med Chem. 2011; 18(18): 1672-703

38. Mielecki M et al, Cinnamic acid Derivatives as Inhibitors of Oncogenic Protein Kinases-structure, mechanisms and Biomedical Effects, Curr Med Chem. 2016; 23(10):954-82   

39. Mielecki M et al, Analogues of cinnamic acid benzyl amide as nonclassical inhibitors of activated JAK2 kinase, Curr Cancer Drug Targets. 2014; 14(7): 638-651    

40. Sova et al, Cinnamic acid derivatives induce cell cycle arrest in carcinoma cell lines. Med Chem 2013 Aug; 9(5): 633-641

41. Reddy ND et al, An appraisal of cinnamyl sulphonamide hydroxamate derivatives (HDAC inhibitors) for anti-cancer, anti-angiogenic and anti-metastatic activities in human cancer cells, Chem Biol Interact. 2016 Jun 25; 253:112-124

42. John a Hoskin, the occurrence, metabolism and toxicity of cinnamic acid and related compounds, Journal of Applied Toxicology December 1984 





Comments

LANDMARK said…
Cinnamic acid is a white crystalline compound with the formula C6H5CH=CHCOOH which is slightly soluble in water, and freely soluble in many organic solvents. It exists as trans and cis isomers, but the trans form is the one most often found in nature and is widely used in commerce. Trans-Cinnamic acid is very important because it is widely used in perfume, food, photographic, polymer and pharmaceutical industries.

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